Endocytosis is a critical mechanism central to, among other processes, receptor desensitization and signal transduction. Available technologies for measuring endocytosis based upon high-content imaging are biologically predictive, but limited in terms of ease of use. In contrast, high throughput screening (HTS)-compatible technologies, such as those utilizing enzyme fragment complementation, require excessive engineering of the biological system, often leading to screening errors (e.g., false negative hits in HTS).